The lingual sense of taste is initially communicated by taste buds, clusters of sensory cells located in highly organized taste papillae, to chemosensory neurons whose cell bodies are located in the geniculate and petrosal ganglia. The chemosensory receptor cells in taste buds continuously turn over and are replaced throughout life. The molecular mechanisms that direct the developmental innervation of taste buds, and maintain these constantly renewing functional connections throughout life, are still being elucidated. Neurotrophic factors are essential for the development and lifelong maintenance of sensory systems. Two members of the neurotrophin family, BDNF and NT-4, are well established as being critical for the survival of geniculate chemosensory neurons, and for their innervation of fungiform taste buds. The members of a second important family of neurotrophic factors, the glial cell line-derived neurotrophic factor (GDNF) family ligands (GFLs), are expressed in the tongue during the period of chemosensory innervation. The GFLs, which consist of GDNF, neurturin, artemin and persephin, are potent neurotrophic factors for subpopulations of somatosensory neurons, spinal motor neurons and autonomic neurons. We recently discovered that the signal-transducing receptor for the GFLs, Ret, is widely expressed in Phox2B+ chemosensory geniculate neurons early in development prior to their innervation of the tongue (greater than 70% at E13.5) and then becomes restricted to a subset (approximately 15%) of Phox2B+ chemosensory neurons in adulthood. This expression profile suggests that the GFL/Ret pathway may have two distinct developmentally regulated functions in the differentiation and maintenance of geniculate chemosensory neurons, but their role in the peripheral taste system is unexplored. Based on preliminary data presented in this proposal, our overarching hypothesis is that the GFL/Ret receptor complex is critically important for the early cell fate determination of geniculate chemosensory neurons, as well as for the life-long maintenance and function of physiologically distinct subpopulations of these neurons. In Specific Aim 1 we will test the hypothesis that GDNF, NRTN and Ret are critical for the developmental specification of chemosensory neurons of the geniculate ganglion, as well as their peripheral innervation of fungiform taste buds. In Specific Aim 2 we will test the hypothesis that the GDNF/Ret receptor complex is necessary for the lifelong maintenance and physiology of a subset of lingual sensory neurons of the geniculate ganglion. Specific Aim 3 will evaluate whether the peripheral taste system degenerates in mouse models of Alzheimer?s disease. The rationale for a mechanistic examination of the GFL/Ret pathway in geniculate neurons is that this may aid in the rational design of therapeutic interventions for diseases, such as Alzheimer?s disease, and injuries of peripheral neurons.